The clearance of virus from infected neurons and recovery from encephalitis does not follow the paradigms which have been found effective in the periphery. Inflammation and swelling must be minimized in order to prevent tissue damage. Thus the well studied destructive mechanisms for handling viral infections are disadvantageous in CNS. We have studied both the specific and innate immune responses of mice to intranasal infection by vesicular stomatitis virus (VSV). We have shown that nitric oxide, produced in infected neurons in vitro, by the neuronal constitutive form of nitric oxide synthase (Type 1), is an effective antiviral agent. We have demonstrated that mice treated with IL-I 2 have a profound dose-related enhancement of recovery from VSV infection. In the work proposed, we will answer two key questions: I) What is the mechanism by which IL-I 2 enhances recovery from VSV infection of the CNS? 2) Is nitric oxide an important biological response molecule in vivo? Our working hypothesis is that IL-I 2 treatment initiates a cascade of cellular responses which include release of IFN-y which subsequently induces many factors, one of the ultimate mediators being activation of nitric oxide synthase. The cellular changes which result from IL-12 treatment promote host cell inhibition of viral replication. The limitation of viral growth is essential, until the specific immune responses can provide Ag-specific T and B cells for long term recovery and protection from subsequent reinfection. This hypothesis will be tested in mice, some of which are deficient in critical components of the cascade (IFN-y, IRF-I, ncNOS, ecNOS). We will test the responses to infection including morbidity and mortality, immunohistochemistry, in situ hybridization, and by plaque assay. The results of these studies will provide important information for the treatment of viral encephalitis of man.